The treatment of Human Immunodeficiency Virus (HIV) infection, known as cause of the acquired immunodeficiency syndrome (AIDS), remains a major medical challenge. Currently available drug therapies include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), HIV-protease inhibitors (PIs), fusion inhibitors and the more recent CCR5 and integrase inhibitors.
Although effective in suppressing HIV, each of these drugs, when used alone, is confronted with the emergence of resistant mutants. This led to the introduction of combination therapy of several anti-HIV agents usually having a different activity profile. In particular the introduction of “HAART” (Highly Active Anti-Retroviral Therapy) resulted in a remarkable improvement in anti-HIV therapy, leading to a dramatic reduction in HIV-associated morbity and mortality. However, none of the currently available combination therapies can completely eradicate HIV. Even HAART can face the emergence of resistance, often due to non-compliance with the prescribed therapy. In these cases HAART can be made effective again by replacing one of its components by one of another class. If applied correctly, HAART combinations can suppress the virus for many years, up to decades, to a level where it no longer can cause the outbreak of AIDS.
One class of HIV drugs often used in HAART is that of the NNRTIs, a number of which are currently on the market and several others are in various stages of development. An NNRTI currently in development is the compound 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino-]-benzonitrile, generically designated as rilpivirine, also known as R278474 or TMC278. This compound not only shows pronounced activity against wild type HIV, but also against many of its mutated variants. The compound TMC278, its pharmacological activity as well as a number of procedures for its preparation have been described in WO 03/16306. The TMC278 described in this reference is in crystalline form and this form will hereinafter be referred to as “Polymorph II” of TMC278. The present invention concerns another polymorphic form of TMC278, which hereinafter will be referred to as “Polymorph I” of TMC278. Polymorph I of TMC278 has previously not been described and is a crystalline form that possesses beneficial properties as will be outlined hereinafter.
Next to activity, the pharmacokinetic profile plays an important role in the effectiveness of any given drug. This in turn coincides with the drug's bioavailability influencing dosing required to reach a therapeutically effective concentration of the drug in a patient. Drugs with a low bioavailability need to be administered in higher doses, thereby increasing the risk of adverse effects. Higher doses further implicate larger dosage forms or an increase in the frequency of administration, or both. These factors may influence adherence to and concomitant effectiveness of anti-HIV treatment. Inadequate treatment in turn increases the risk of emergence of mutant HIV strains.
TMC278 has a relatively low solubility in water resulting in poor bioavailability. Unexpectedly, it has now been found that a new crystalline form of TMC278 has an increased intrinsic dissolution rate and higher solubility in acidic aqueous media. These properties are beneficial as regards bioavailability making the new crystalline form attractive for application in solid dosage forms, but also in certain liquid dosage forms such as aqueous dispersions. The latter may find use in formulations for parenteral administration.
In addition, the use of a particular polymorphic form of an active ingredient is recommendable because the composition of polymorphic mixtures may vary from batch to batch or may vary in time thereby causing changes in the properties of that active ingredient. If the polymorphic form is not held constant during clinical and stability studies, the exact dosage used or measured may not be comparable from one lot to the next. Once a pharmaceutical compound is produced for human use, it is important to recognize the polymorphic form delivered in each dosage form to assure that the production process uses the same form and that the same amount of drug is included in each dosage. Therefore, it is necessary to assure that either a single polymorphic form or some known combination of polymorphic forms is present.
Currently used anti-HIV drugs require frequent administration of relatively high doses. The number and/or volume of dosage forms that need to be administered are commonly referred to as the “pill burden”. A high pill burden causes patients to fail to comply with the prescribed dosage regimen thereby not only reducing the effectiveness of the treatment but also causing the emergence of resistant mutants. Hence there is a need for anti-HIV therapy that avoids a high pill burden, involving the administration of dosage forms of relatively small size not requiring frequent dosing. It would be further desirable to provide anti-HIV therapy that can be administered at long time intervals such as a week, a month, or longer.
Current therapies do not allow to completely eradicate HIV so that individuals infected with HIV pose a continuous risk of infecting others. After initial infection it takes a long time before the outbreak of the first symptoms of AIDS. People may live for years with the infection without experiencing any effects of it thereby being unaware of the risk of further transferring the virus to others. Prevention of HIV transmission therefore is crucial because of the imminent risk of individuals being in contact with HIV infected persons of becoming infected. This in particular is the case for those providing medical care to infected patients such as physicians, nurses or dentists. Another group of individuals at risk are breast-fed infants whose mother is infected or at risk of becoming infected, especially in developing countries where alternatives for breast-feeding are less obvious. Hence there is a need for easy to apply means that provide effective prevention against transmission of HIV. Providing such prevention means is a further object of the present invention.
The crystalline form of TMC278 subject of this invention can be formulated into micro- or nanoparticles that function as depot formulations in the treatment of HIV infection as well as in the prevention of transmission of HIV. Nanoparticles of drug substances are known having been described e.g. in EP-A-0 499 299. It has been found that micro- or nanoparticle formulations of Polymorph I of TMC278 can be administered intermittently at time intervals of one week or longer resulting in plasma levels sufficient to suppress multiplication of HIV. The number of administrations is reduced thereby, which is beneficial in terms of pill burden and drug compliance of the patient. Such micro- or nanoparticle formulations may find use in the long-term treatment or prevention of HIV.
Because of its beneficial properties, Polymorph I of TMC278 is particularly suited for use in micro- or nanoparticle formulations. Such formulations are expected to result in higher blood plasma levels for a given amount of TMC278 administered. Moreover, the desired blood plasma levels will be reached quicker. Relatively high blood plasma levels may be required where high safety margins are desired.